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A potentiometric investigation has been carried out to disclose the coordination properties of Dacarbazine, 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide (abbreviated DTIC) with particular transition metal ions (Zn2+, Cu2+, Ni2+ and Co2+). The coordination of DTIC with these metal ions results in several complexes emerging in solution. The aim of this work is to determine the protonation constants of the DTIC and to show the extent of its coordination with (Zn2+, Cu2+, Ni2+ and Co2+), in other words, establish the stability of the complexes formed between the DTIC and these metal ions by the determination of their stability constants. Experimental environments were organized to attain the coordination and measurements in aqueous solutions at 25±0.1 °C and an ionic background of 0.1 mol dm-3 NaCl. The HYPERQUAD computer program was used to determine both the protonation and stability constants for the ligand and metal-ligand complexes respectively. DTIC has five protonation constants that can be obtained under experimental conditions used; 10.54, 20.15, 26.99, 32.02 and 36.01. The results are interpreted in terms of the basicity of the donor atoms and structural composition of the ligand. All the complexes produced in the solution are exhibited in speciation diagrams. [ABSTRACT FROM AUTHOR]

This article aims to investigate the knowledge about Digital Technologies of Information and Communication (DTIC) in the initial training of pedagogues. The data of the documentary research were collected at public universities of São Paulo State, particularly at those that offer undergraduate courses in pedagogy in face-to-face modality. Documents that contextualize the legal scenario on teachers training and the pedagogical projects of the selected courses were analyzed, including their curricular structure and teaching plans for the subjects that discuss DTIC. Documentary analysis is based on the qualitative approach and the principles of Content Analysis (BARDIN, 1977). The results point to the need for curricular updates, which collaborates to put the theme in perspective and at the center of educational debates about teachers training. [ABSTRACT FROM AUTHOR]

Abstract Background Cytotoxic chemotherapy combinations and targeted agents represent established treatment concepts in advanced pancreatic neuroendocrine tumors (PNETs). However, response rates, side effects and outcome data strongly vary among these therapeutic approaches. Head-to-head comparisons between chemo- and molecular therapies are missing and secondary resistances frequently occur. The RamuNET trial aims to identify the effectiveness of dual treatment with DTIC and ramucirumab in progressive advanced PNET patients. Methods The RamuNET study is an investigator-initiated multicenter prospective single-arm trial to evaluate the efficacy of ramucirumab in combination with dacarbazine (DTIC) over a period of at least 6 months. Patients with progressive well-differentiated and metastatic pancreatic neuroendocrine tumors are eligible. The study aims to include 45 patients over a period of 24 months with a minimum follow-up of 24 months. The primary endpoint is disease control after 6 months. Secondary endpoints include progression-free survival, biochemical response, overall survival, quality of life and toxicity. Based on the hypothesis that 80% of the patients can achieve a disease control after 6 months, the sample size calculation follows an exact binomial single-stage design. H0: p =p1 = 80%, alpha = 0.05, beta = 0.1. Discussion This study investigates a new therapeutic approach using the combination of cytotoxic and targeted antiangiogenic therapy in advanced PNET. If positive, this trial will be the basis for a randomized two-arm study to investigate the combination of ramucirumab and DTIC against other established therapies in PNET. Trial registration EudraCT: 2017–001207-68 . Date of registration: 2018.01.03.

Background: Cytotoxic chemotherapy combinations and targeted agents represent established treatment concepts in advanced pancreatic neuroendocrine tumors (PNETs). However, response rates, side effects and outcome data strongly vary among these therapeutic approaches. Head-to-head comparisons between chemo- and molecular therapies are missing and secondary resistances frequently occur. The RamuNET trial aims to identify the effectiveness of dual treatment with DTIC and ramucirumab in progressive advanced PNET patients.Methods: The RamuNET study is an investigator-initiated multicenter prospective single-arm trial to evaluate the efficacy of ramucirumab in combination with dacarbazine (DTIC) over a period of at least 6 months. Patients with progressive well-differentiated and metastatic pancreatic neuroendocrine tumors are eligible. The study aims to include 45 patients over a period of 24 months with a minimum follow-up of 24 months. The primary endpoint is disease control after 6 months. Secondary endpoints include progression-free survival, biochemical response, overall survival, quality of life and toxicity. Based on the hypothesis that 80% of the patients can achieve a disease control after 6 months, the sample size calculation follows an exact binomial single-stage design. H0: p < =p0 = 60% versus H1: p > =p1 = 80%, alpha = 0.05, beta = 0.1.Discussion: This study investigates a new therapeutic approach using the combination of cytotoxic and targeted antiangiogenic therapy in advanced PNET. If positive, this trial will be the basis for a randomized two-arm study to investigate the combination of ramucirumab and DTIC against other established therapies in PNET.Trial Registration: EudraCT: 2017-001207-68 . Date of registration: 2018.01.03. [ABSTRACT FROM AUTHOR]

Unemployment and poverty is one of the burning problems of Indian society especially in rural area. The non form sector of rural area is playing a important role against unemployment and poverty elevation. The rural non form sector is also playing a role against migration of labour from rural to urban habitat. There are so many Govt. schemes which are working against the poverty but PMEGP is the only scheme which promotes industry and employment. PMEGP the introduction of a new credit linked subsidy program called Prime Minister's Employment Generation Program (PMEGP) for unemployment Youth. PMEGP Scheme objective of prevent migration of Rural population to Urban with promoting more industry in Rural area hence more employment is generated in Rural Area. PMEGP Scheme objective of prevent migration of Rural population to Urban with promoting more industry in Rural area hence more employment is generated in Rural Area. Rural development will be successful only when it goes along with the development of infrastructural development, employment generation and Human resource, Therefore, it is necessary to study the Effectiveness of PMEGP Scheme on Development of Micro and Small Enterprises in District Bilaspur. [ABSTRACT FROM AUTHOR]

The Defense Technical Information Center (DTIC) celebrates its 75th anniversary in 2020. In that time DTIC has collected, preserved and provided the Department of Defense (DoD) access to its accumulated collection of scientific and technical information. Information formats have changed significantly in three quarters of a century from paper to microfilm/microfiche to electrons. Similar to other information providers, DTIC has needed to adapt and innovate to a new and continually changing technology landscape. In order to keep pace in the information arena, DTIC moved from passively collecting documents on completed research, to actively producing products that expand view of the lifecycle of research, provide collaborative tools, and enable the analysis of trends in budget and research. This article will explore the history, processes, and current services offered by this pioneering and unique information agency. As the organization reflects on its accomplishments, it looks to the future of serving DoD information needs. DTIC will continue to preserve research for use by the DoD scientific community, with an eye toward developing new ways to analyze this body of information. [ABSTRACT FROM AUTHOR]

Background: Canine histiocytic sarcoma (HS) is an aggressive neoplasm that is generally associated with a poor prognosis. CCNU is considered first-line medical therapy, although the majority of dogs ultimately develop progressive disease. The objective of this study was to evaluate the efficacy of dacarbazine as a rescue agent for HS. Materials and Methods: Medical records of dogs diagnosed with HS that received at least one dose of dacarbazine were reviewed. Information collected and analyzed included signalment, disease distribution, treatment history, dacarbazine treatments (including dose, interval and total number of cycles), adverse events, and response to treatment. Results: Seventeen dogs were included, all of which had disseminated or metastatic disease and had received prior treatment with CCNU. Three dogs achieved partial remission for an overall response rate of 17.6%. The overall median event-free survival (EFS) was 21 days. For dogs that experienced an objective response, the EFS was 70 days. Toxicity secondary to dacarbazine was generally mild and self-limiting. Conclusion: In the setting of advanced disease, dacarbazine appears to have modest activity against HS and warrants further investigation. [ABSTRACT FROM AUTHOR]

Treatment of advanced soft tissue sarcoma usually includes dacarbazine (DTIC), an alkylating agent that methylates DNA and is active during all phases of the cell cycle. Common side effects of DTIC include nausea, vomiting, impaired liver and kidney function, myelosuppression, and pneumonia. There are no accounts, however, of histological and hematological changes caused by DTIC. We investigated acute hematological and morphological changes in different organs and in tumors that were caused by a single dose of DTIC. Adult Syrian golden hamsters were inoculated with a suspension of tumorigenic baby hamster kidney (BHK) cells by subcutaneous injection. On day 14 after inoculation, doses of 1.4, 1.6, 1.8 or 2.0 g/m2 DTIC were injected intraperitoneally into the hamsters. Hamsters in the control group were injected with physiological saline in the same way. Seven days after drug or saline injection the animals were sacrificed and samples of blood, heart, kidney, liver, lungs, spleen, small intestine and tumor were excised, processed and analyzed. Mitoses were counted using an ocular extension with engraved frame. Anemia, thrombocytopenia and leukocytosis were found in the control group of hamsters with fibrosarcoma, whereas animals with fibrosarcoma treated with DTIC developed anemia, thrombocytopenia and leukopenia. Severe pneumonia and moderate hepatitis were detected in all DTIC treated groups. Effects of DTIC on tumor cells included rounding and enlargement of nuclei and rarefaction of chromatin. The number of mitoses was reduced with increasing doses of DTIC. Hepatitis, myelosuppression, pneumonia, and dose-related inhibition of tumor cell proliferation were observed after a single dose of DTIC. [ABSTRACT FROM AUTHOR]

Abstract: Background The treatment of melanoma, an aggressive, chemo-resistant skin cancer characterized by rapid metastasis and a poor prognosis, requires the development of innovative therapies with improved efficacy. The p53R2 gene that encodes the ribonucleotide reductase small subunit 2 homologue is induced by several stress signals including DNA-damaging agents that activate p53. The p53R2 gene product increases the deoxynucleotide triphosphate pool in the nucleus; this facilitates DNA repair and synthesis. Objective We examined the expression of p53R2 in melanoma and evaluated whether p53R2 is involved in the growth and proliferation of melanoma cells. Methods We examined the clinicopathological significance of p53R2 in melanoma. To investigate the role of p53R2 in melanoma we used KHm5 and KHm6 melanoma cells that express p53R2, and p53R2-targeting small interfering (si) RNA. Results p53R2 expression was detected immunohistochemically in 56 of 78 patients (71.8%). The expression of p53R2 was significantly correlated with the depth of invasion and the tumor stage. p53R2-targeting siRNA successfully knocked down p53R2 and significantly inhibited the growth of KHm5 and 6 cells. Moreover, The degree of KHm5 and 6 cell growth inhibition was greater in the presence of both p53R2-targeting siRNA and nimustine (ACNU) than with ACNU alone, suggesting that p53R2 silencing enhanced the chemosensitivity of KHm5 and 6 cells to ACNU. Conclusions We propose p53R2 as a therapeutic target to enhance the effectiveness of chemotherapy in patients with p53R2-positive melanoma. [Copyright &y& Elsevier]

Metastatic melanoma responds poorly to systemic treatment. We report the results of a prospective single institution study evaluating O6-methylguanine-DNA methyltransferase (MGMT) status as a potential predictive and/or prognostic marker among patients treated with dacarbazine (DTIC) 800–1000mg/m2 monotherapy administered as a 3-weekly schedule for advanced malignant melanomas. The study was approved by the Regional Ethical Committee. Surgical biopsies from metastatic or loco-regional deposits obtained prior to DTIC treatment were snap-frozen immediately upon removal and stored in liquid nitrogen up to processing. Median time from enrolment to end of follow-up was 67months. MGMT expression levels evaluated by qRT-PCR correlated significantly to DTIC benefit (CR/PR/SD; p =0.005), time to progression (TTP) (p =0.005) and overall survival (OS) (p =0.003). MGMT expression also correlated to Breslow thickness in the primary tumour (p =0.014). While MGMT promoter hypermethylation correlated to MGMT expression, MGMT promoter hypermethylation did not correlate to treatment benefit, TTP or OS, suggesting that other factors may be critical in determining MGMT expression levels in melanomas. In a Cox proportional regression analysis, serum lactate dehydrogenase (LDH, p <0.001), MGMT expression (p =0.022) and p16INK4a expression (p =0.037) independently predicted OS, while TTP correlated to DTIC benefit after 6weeks only (p =0.001). Our data reveal MGMT expression levels to be associated with disease stabilisation and prognosis in patients receiving DTIC monotherapy for advanced melanoma. The role of MGMT expression as a predictor to DTIC sensitivity versus a general prognostic factor in advanced melanomas warrants further evaluation. [Copyright &y& Elsevier]

Metastatic melanoma is considered to be one of the most resistant tumors to standard chemotherapy approaches nowadays. Old anti-cancer treatments like dacarbacin (DTIC) or interleukin-2 (IL-2) continue to be the only approved treatments by the main worldwide health authorities. Up to now, no combination or new anti-targeted agent has shown an improvement in overall survival when compared to either of these two drugs alone. In fact, more than a dozen phase III randomized trials have tried to go beyond these old approaches, without meeting any success. Despite the fact that the median overall survival of patients diagnosed with metastatic melanoma is lower than 9 months, melanoma emerges as a challenging disease for testing new drugs and implementing the deeper knowledge in the molecular biology underlying this tumor. New immunotherapeutic targets have appeared recently trying to modulate the host immune response against the tumor. Furthermore, in the last three years, new targeted agents have changed the standard of care of other solid tumor types like renal cancer. We wonder if these new agents will be incorporated in the standard management of advanced melanoma patients in the coming years. [ABSTRACT FROM AUTHOR]

Dacarbazine (DTIC) has been used for the treatment of melanoma for decades. However, monotherapy with this chemotherapeutic agent results only in moderate response rates. To improve tumor response to DTIC current clinical trials in melanoma focus on combining a novel targeted agent with chemotherapy. Here, we demonstrate that tyrosinase which is commonly overexpressed in melanoma activates the bioflavonoid quercetin (Qct) and promotes an ataxia telangiectasia mutated (ATM)-dependent DNA damage response. This response sensitizes melanoma cells that overexpress tyrosinase to DTIC. In DB-1 melanoma cells that overexpress tyrosinase (Tyr+ cells), the threshold for phosphorylation of ATM and p53 at serine 15 was observed at a low dose of Qct (25 μM) when compared to the mock transfected pcDNA3 cells, which required a higher dose (75 μM). Both pcDNA3 and Tyr+ DB-1 cells demonstrated similar increases in phosphorylation of p53 at other serine sites, but in the Tyr+ cells, DNApk expression was found to be reduced compared to control cells, indicating a shift towards an ATM-mediated response. The DB-1 control cells were resistant to DTIC, but were sensitized to apoptosis with high dose Qct, while Tyr+ cells were sensitized to DTIC with low or high dose Qct. Qct also sensitized SK Mel 5 (p53 wildtype) and 28 (p53 mutant) cells to DTIC. However, when SK Mel 5 cells were transiently transfected with tyrosinase and treated with Qct plus DTIC, SK Mel 5 cells demonstrated a more than additive induction of apoptosis. Therefore, this study demonstrates that tyrosinase overexpression promotes an ATM-dependent p53 phosphorylation by Qct treatment and sensitizes melanoma cells to dacarbazine. In conclusion, these results suggest that Qct or Qct analogues may significantly improve DTIC response rates in tumors that express tyrosinase. [ABSTRACT FROM AUTHOR]

Background and objective: Some anticancer drugs can result in increased production of reactive oxygen species (ROS). Alkylating agents are the most frequently used drugs in chemotherapeutic regimens for the treatment of malignant melanoma. It is known that triazenes exhibit in vivo activity by alkylation of nucleic acids and proteins, but there is no data about ROS formation during oxidative metabolism. Single agents of most interest for treatment of malignant melanomas include 5-(3,3-dimethyltriazene-1-yl)-imidazole-4-carboxamide (DTIC) and nitrosoureas such as 1-(2-chloroethyl) -3-cyclohexyl-1-nitrosourea (CCNU), but complete response to these drugs is rare. The present study aimed to determine whether an oxidative stress occurs during the clinical course of melanoma and the influence of therapy on the antioxidant status of patients with melanoma. For this purpose, we investigated plasma concentrations of MDA as indices of the levels of lipid peroxidation products. In addition, we studied the activities of the antioxidant enzymes superoxide dismutases (SOD) and catalase (CAT) in patients with melanoma before any treatment, after surgical removal of melanoma, and after chemotherapy with DTIC or in combination with CCNU of the operated patients. Methods: Twenty one patients with melanoma were studied. Patients were operated prior to chemotherapy. After recovery for 10–20 days postoperatively, they were studied again for MDA, SOD and CAT activity. The patients were divided into two groups according to the chemotherapy (3–7 treatment cycles): with DTIC – given orally daily for 5 days, every 3 weeks as a single 2200 mg/kg dose and with the combination – DTIC (the same dose) + CCNU – administered orally at a dosage of 120 mg/m2 once every 40 days in accordance with protocols, approved by the Bulgarian Ministry of Health. The total amount of lipid peroxidation products in plasma was assayed. Results and discussion: Plasma levels of MDA and CAT activity were significantly higher, and erythrocyte SOD activity significantly lower, in patients with melanoma, than in control healthy volunteers ( P < 0·0001). Ten to twenty days after surgery, oxidative stress decreased but levels of MDA increased as a result of therapy. Important sources of increased ROS production may be the monocytes, phagocytosis of tumour cells and the cancer tissues. Plasma MDA in patients treated with DTIC + CCNU were significantly higher ( P < 0·001), but erythrocyte SOD statistically lower ( P < 0·00001), compared with patients treated with DTIC only. However, a combination of DTIC + CCNU did not attenuate oxidative stress, or reduced antioxidant status. Patients treated with this combination are at bigger risk of oxidative injury. Therefore, this disturbance might be due to augmented generation of toxic ROS, possibly from the metabolism of CCNU. Conclusion: Increased oxidative stress follows an imbalance in antioxidant defence in non-treated patients with melanoma. The impaired antioxidant system favours accumulation of ROS, which may promote the cancer process . After complete removal of melanoma tissues, oxidative stress decreased. The antioxidant status of melanoma patients operated on was influenced by the different chemotherapeutic regimens used and may play an important role in the response. Patients on DTIC + CCNU are at higher risk of oxidative injury. This drug combination probably exerts its toxic activity by ROS, which could be products of the metabolism of CCNU. [ABSTRACT FROM AUTHOR]

Summary: Background: Advanced melanomas (non-resectable Stage-III/IV) are fatal, with few effective treatments. It remains unclear if other drugs offer improvements over the standard, dacarbazine. Purpose: We quantified objective response rates (Complete+Partial response) of dacarbazine versus comparators for advanced cutaneous melanoma. Methods: We retrieved all head-to-head randomized controlled trials involving dacarbazine and other drugs/combinations. Two reviewers searched MEDLINE (1966–Jan 2006), EMBASE (1980–2006), CINAHL (1982–2006) and Cochrane library, then compared results. Differences were resolved through consensus. Rates were combined using random effects meta-analysis. χ 2 tested heterogeneity; points from Jadad’s method were assessed to examine study quality. Results: We found 48 studies having 111 active treatment arms [24 with dacarbazine monotherapy (n =1390), 75 with dacarbazine combinations (n =4962), and 12 with non-dacarbazine treatments (n =783)] treating 7135 patients. Overall, study quality was poor. Response to dacarbazine monotherapy ranged between 5.3% and 28.0% (average 15.3%), OR=1.31, CI95%: 1.06–1.61; N =3356. Partial responses comprised 73% of successes. Only adding interferons improved response rates (OR=1.69, CI95%: 1.07–2.68, N =778) but survival duration was not significantly longer (P =0.32), and trials with larger sample sizes found lower success rates. All other treatments alone or in combination were ineffective P >0.05. Conclusions: Dacarbazine generally produces poor outcomes. Adding other therapies offers minimal clinical advantages (possibly with interferons). In general, study quality was poor and sample sizes were small. This meta-analysis highlights the unmet need for effective treatment options for advanced melanoma. [Copyright &y& Elsevier]

Purpose: Based on the promising results of a Phase I study with a combination of gemcitabine and DTIC performed in advanced soft tissue sarcoma (ASTS) patients, and due to the limited efficacy of second or third line therapies in those patients, we designed a Phase II study to determine the activity of this new regimen. Methods: Patients with ASTS, measurable disease, pretreated with chemotherapy, received gemcitabine 1,800 mg/m2 infused over 180 min followed by DTIC 500 mg/m2 (one cycle), every 2 weeks. The pharmacokinetics (PK) of gemcitabine and 2′,2′-difluorodeoxyuridine (dFdU), and the accumulation of gemcitabine triphosphate (dFdCTP) by peripheral blood mononuclear cells were studied. The influence of the sequence of administration on those parameters was examined to exclude potential drug interactions. Results: Twenty-six patients received a total of 158 cycles (mean four cycles, range 1–18). Grade 3–4 anemia (23% of patients), granulocytopenia (46%) or thrombocytopenia (12%), and grade 3 increase in AST (18%), ALT (21%), or γ-glutamyl-transferase (9%) were noted. Response rate in 23 patients was 4% (95% CI: 0–24%), and in 8 of 11 patients stable disease lasted > 6 months. Progression-free rate (PFR) at 3 and 6 months was, respectively, 48 and 28%, and median overall survival 37 weeks. Pooled data from the Phase I and Phase II studies showed clinical benefit in patients with leiomyosarcomas (LMS) (57%) and malignant fibrous histiocytomas (MFH) (33%). The sequence of administration did not influence PK of gemcitabine or dFdU. There was a trend ( P = 0.11) toward a lower accumulation of dFdCTP when DTIC preceded gemcitabine. Conclusions: Although the remission rate was low, PFR figures indicate that this regimen has activity in patients with ASTS. It should be compared with DTIC, or other gemcitabine-containing combinations, in patients with LMS or MFH, to determine whether this combination offers advantages in PFR or in overall activity. [ABSTRACT FROM AUTHOR]

Since dacarbazine was approved for treating metastatic melanoma in the 1970s, numerous studies have evaluated whether different schedules and dacarbazine-based combinations improve clinical outcomes. This evidence-based review shows that combining dacarbazine with other drugs having single-agent activity and/or hormonal or immunotherapeutic compounds fails to provide clinically meaningful improvements in survival, and may increase toxicity. In patients with metastatic melanoma, dacarbazine was previously administered in cycles of multiple consecutive daily infusions per cycle. The introduction of potent antiemetics, together with concerns relating to patient comfort and clinic utilisation time, has enabled regimens involving single-dose dacarbazine, administered at the same total dose per cycle. These appear to be as effective as multiple-dose schedules, are well tolerated, and are more straightforward to administer. Single-administration dacarbazine (850–1000 mg/m2), once every 3 weeks, is currently the standard reference therapy in patients with advanced melanoma. New effective therapies are urgently needed for this treatment-refractory disease. [Copyright &y& Elsevier]

We have studied the toxic effect of the alkylating antitumor drug N′-cyclohexyl-N-(2-chloroethyl)-N-nitrosourea (lomustine, CCNU) on Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) strains, alone and in presence of oxygen radical-scavenging substances [Vitamin E, stable nitroxyl radical 2,2,6,6-tetramethylpiperidine-N-oxyl (TMPO), and spin labeled (nitroxyl free radical moiety containing) analogues of CCNU] and compared with that of the alkylating antitumor drug 5-(3,3-dimethyltriazene-1-yl)-imidazole-4-carboxamide (dacarbazine, DTIC). All spin labeled compounds tested were almost no toxic at doses of 50–500 μM/ml, whereas the alkylating antitumor drug CCNU showed toxicity in a dose dependent manner. Even low doses of spin labeled nitrosoureas provided protection against the toxicity caused by the antitumor drug CCNU alone. The lowest toxicity against E. coli and S. aureus were achieved when 500 μM/ml of CCNU was combined with 200 μM/ml of spin labeled nitrosourea N-[N′-(2-chloroethyl)-N′-nitrosocarbamoyl]-glycine amid of 2,2,6,6-tetramethyl-4-aminopiperidine-1-oxyl (SLCNUgly). A combination of TMPO with vitamin E completely abolished the toxicity of CCNU. Endogenous formation of oxygen radicals and their possible involvement in CCNU toxicity towards the bacteria strains tested have been also discussed. [Copyright &y& Elsevier]

We conducted a randomized phase II study to determine the efficacy of dacarbazine (DTIC) in recurrent gliomas. Patients were randomly assigned to receive either DTIC 750 mg/m2 IV day 1 every 28 days (Arm A) or DTIC 200 mg/m2 IV days 1–5 every 28 days (Arm B). Pharmacokinetics were studied in 6 patients on each arm using HPLC analysis. Thirty-nine patients (30 male, 9 female), ages 27–67 years (median 53) were entered on the study (20 on Arm A, 19 on Arm B). No objective responses were seen. Median time to progression was 3 months. Median survival was 8 months. Treatment was generally well tolerated. Major toxicities were grade 1–2 nausea (33%), lethargy (28%), diarrhea (15%), alopecia (15%), and grade 3 neutropenia (8%). Four patients on Arm A had mild self-limited episodes of intravascular hemolysis occurring immediately after drug infusion, the mechanism of which is unknown. Mean AUC for DTIC, HMMTIC (5-[3-hydroxymethyl-3-methyl-1-triazeno] imidazole-4-carboxamide), and MTIC (5-[3-methyl-1-triazeno] imidazole-4-carboxamide), in Arm A were 14.8, 0.17, and 1.15 mM min, respectively. Corresponding values for Arm B (on day 1 of 5) were 1.7, 0.06, and 0.29 mM min, respectively. The predicted HMMTIC and MTIC exposure over 5 days for Arm B, based on the day 1 data, is higher than with Arm A. We conclude that DTIC is well tolerated but does not have activity in patients with recurrent gliomas. The 5-day schedule appears less toxic, and pharmacokinetic studies show that it provides greater exposure to MTIC and HMMTIC compared to the one-day schedule. [ABSTRACT FROM AUTHOR]

We report results of a conservative treatment for brain metastases from malignant melanoma with a combination of irradiation and chemotherapy (fotemustine and/or DTIC). To date, 12 patients have been treated. There was a complete remission of the brain metastases in four patients. In two patients a partial remission was observed. The mean survival of the responder was 8.2 months (95% confidence interval 3.8–12.6 months). The most common side effects were thrombocytopenia, leukopenia, and alopecia. Altogether, the treatment was well tolerated. As the outcome of patients with brain metastases from malignant melanoma is generally poor, this combined chemo- and radiation therapy may provide improved care for such patients. [ABSTRACT FROM AUTHOR]

We report the effects of one cytostatic and one anti-emetic, DTIC and chlorpromazine (CPZ), on eight established human melanocyte cell lines using 3 methods of evaluation. Considerable differences in chemosensitivity to DTIC were discovered. Both inhibition, stimulation and no effect were seen. CPZ always showed cytotoxic effect in vitro. DTIC combined with CPZ had an antagonistic effect except for one cell line which was synergistic. From the chemosensitivity obtained with a primary tumor, it was impossible to predict that of its metastasis. Two similar metabolic effects in vitro were not necessarily related to identical therapeutic sensitivity in vivo. At least 3 significant results must be obtained in vitro to predict a therapeutic schedule. [ABSTRACT FROM AUTHOR]

A prospectively randomized trial was undertaken to compare dacarbazine (DTIC) alone with DTIC plus interferon in patients with metastatic malignant melanoma. Of the 73 patients who entered on the study, 36 were randomized to receive DTIC alone and 37 were randomized to receive the combination DTIC plus interferon. The two sections were well balanced. There was more toxicity on the combination section, but no life threatening toxicity. The overall response rate for patients on DTIC was 20% (two complete and five partial responses) (95% CI 7-39%) and for patients on DTIC plus interferon was 50% (13 complete and four partial responses) (95% CI 26-72%) (p = 0.007). The median time to treatment failure, was significantly more in favour of the combination treatment (9 versus 2.5 months; p < 0.01, Mantel-Cox). The median survival of 16.7 versus 8 months was in favor of the combination treatment (p < 0.01). The reasons for the improved results with the combination treatment are discussed. The Eastern Cooperative Oncology Group is currently, based on the results of this study, investigating the role of interferon combinations in metastatic malignant melanoma. [ABSTRACT FROM AUTHOR]

The prognosis of patients with malignant melanoma and brain metastases is poor. Therapy of brain metastases is difficult and mostly unsuccessful, with brain metastases being the predominant factor which determines overall survival. We report here on a patient whose brain metastases responded to DTIC+INF-gamma. We present a short summary on the different effects on INF-alpha and INF-gamma and reach the conclusion that clinical trials which combine DTIC and INF-gamma should be performed. Based on this observation, combinations including INF-alpha are not necessarily comparable to modalities which include INF-gamma. [ABSTRACT FROM AUTHOR]

Background: In the precheckpoint inhibitor era, high-dose interferon was the only approved adjuvant therapy for high-risk melanoma. In this manuscript, we analyze the recurrence-free survival, overall survival and toxicity profile of adjuvant treatment with interleukin-2 (IL-2) and 5-(3,3-dimethyle-1-triazeno) imidazole-4-carboxamide (DTIC) for resected high-risk melanoma patients., Methods: All patients with stage IIB, IIC or stage III melanoma who were treated with DTIC/IL-2 combination therapy at a single institution from 2000 to 2010 were identified from the University of Louisville Hospital medical record. Patients received 6 months of subcutaneous IL-2 (12 × 10 6 units days 1-4) and intravenous DTIC (750 mg/m 2 day 1 of each cycle) every 28 days for 6 cycles. Individual medical records were accessed to collect the data., Results: Of the 112 patients treated, all underwent surgical resection and then received adjuvant treatment. A total of 58.7% of the patients were male, 42.2% female; 99% were Caucasian. A total of 79 (72.5%) of the patients were alive at the time of analysis and 57 (47.7%) patients were currently event free. A total of 69 (63.3%) patients completed all 6 months of adjuvant combination treatment with 13.8% of the patients requiring IL-2 and 21.1% of the patients requiring DTIC dose reduction. Five year overall survival was 75.57% with recurrence-free survival of 53.05%., Conclusions: For several decades, there has not been an ideal adjuvant treatment for patients with resected high risk melanoma. Our retrospective analysis suggests that combination therapy with DTIC/IL-2 is beneficial and relatively well tolerated as an alternative adjuvant treatment for patients with high-risk melanoma., (Copyright © 2018. Published by Elsevier Inc.)

The article discusses a treatment regimen for nodular melanoma with local spread, which used a well tolerable intravenous monochemotherapy and local therapy with diphenylcyclopropenone and radiation. Local control of the large primary melanoma and stabilization of satellites were observed after three treatment cycles and almost complete clearance was seen after 10 cycles. Treatmetn can be discontinued after 15 cycles in as many months and complete clearance of all lesions.

Background/aim: Alkylating chemotherapeutics with either a streptozotocin-(STZ) or temozolomide-(TEM) backbone are routinely used in patients with progressive and unresectable pancreatic neuroendocrine tumors (PNET). In addition, dacarbazine (DTIC) was described as an alternative alkylating therapy option for PNETs. The optimal treatment sequence with alkylating compounds and a potential use of O6-methylguanine-DNA methyltransferase (MGMT) level as predictive biomarker have not yet been sufficiently elucidated. The aim of our study was the evaluation of therapy sequence with either STZ-based treatment followed by DTIC (group A) or the inverse schedule with upfront DTIC (group B) and to correlate MGMT status with clinicopathological characteristics and response to therapy., Patients and Methods: We retrospectively analyzed 28 patients with neuroendocrine tumors (NET) who were treated with STZ-based therapy and DTIC. Additionally, in a second group MGMT immunohistochemistry was performed from primary and metastatic tumor sites. For statistical evaluation Kaplan-Meier analysis, Cox regression methods and Fisher's exact test were used., Results: There was no difference of objective response and disease control between either STZ-based therapy followed by DTIC treatment (group A) after progression or the reverse sequence (group B). Median time to progression (TTP) was estimated to be 21 months in both arms. First-line STZ-based chemotherapy was not superior to first-line DTIC treatment (16 vs. 13 months; p=0.8). MGMT status did not correlate with clinicopathological characteristics or response to therapy with these alkylating agents., Conclusion: Upfront chemotherapy with either STZ-based treatment or DTIC monotherapy showed similar efficacy and median TTP rates. In this study, MGMT protein expression assessed by immunohistochemistry did not play an important role as a predictive marker for alkylating agents., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: There is currently no curative treatment for melanoma once the disease spreads beyond the original site. Although activation of the PI3K/Akt pathway resulting from genetic mutations and epigenetic deregulation of its major regulators is known to cause resistance of melanoma to therapeutic agents, including the conventional chemotherapeutic drug dacarbazine and the Food and Drug Administration-approved mutant BRAF inhibitors vemurafenib and dabrafenib, the role of extracellular stimuli of the pathway, such as insulin, in drug resistance of melanoma remains less understood., Objective: To investigate the effect of insulin on the response of melanoma cells to dacarbazine, and in particular, the effect of insulin on the response of melanoma cells carrying the BRAF(V600E) mutation to mutant BRAF inhibitors. An additional aim was to define the role of the PI3K/Akt pathway in the insulin-triggered drug resistance., Methods: The effect of insulin on cytotoxicity induced by dacarbazine or the mutant BRAF inhibitor PLX4720 was tested by pre-incubation of melanoma cells with insulin. Cytotoxicity was determined by the MTS assay. The role of the PI3K/Akt pathway in the insulin-triggered drug resistance was examined using the PI3K inhibitor LY294002 and the PI3K and mammalian target of rapamycin dual inhibitor BEZ-235. Activation of the PI3K/Akt pathway was monitored by Western blot analysis of phosphorylated levels of Akt., Results: Recombinant insulin attenuated dacarbazine-induced cytotoxicity in both wild-type BRAF and BRAF(V600E) melanoma cells, whereas it also reduced killing of BRAF(V600E) melanoma cells by PLX4720. Nevertheless, the protective effect of insulin was abolished by the PI3K and mTOR dual inhibitor BEZ-235 or the PI3K inhibitor LY294002., Conclusion: Insulin attenuates the therapeutic efficacy of dacarbazine and PLX4720 in melanoma cells, which is mediated by activation of the PI3K/Akt pathway and can be overcome by PI3K inhibitors.

A potential anti-melanoma prodrug containing a phenolic activator, a hydrazine linker, and a nitrogen mustard effector - (N-{4-[bis-(2-chloroethyl)amino]benzoyl}-N'-(4-hydroxybenzyl)hydrazine) has been synthesized in seven steps. Spectrophotometric measurements of its oxidation by tyrosinase showed a rapid increase of absorbance at 337 nm. HPLC analysis demonstrated that two major products were formed. However, during the reaction one of the products was converted into the other. The stable product with a maximum of absorption at 337 nm was isolated and identified as 5,6-dihydroxy-1H-indazol-1-yl 4-[bis-(2-chloroethyl)amino]benzoate. It was formed by a cyclization of the enzymatically generated o-quinone. This reaction was unexpected, since the acylated hydrazine nitrogen atom should not be sufficiently nucleophilic to attack the o-quinone ring. This cyclization prevented the effector release from the enzyme-activated prodrug. As a result, the prodrug showed only limited specificity for B16-F10 murine melanoma cells compared to reference cell lines. When applied in solid tumors in mice it showed slightly higher activity than the parent mustard drug (4-[bis-(2-chloroethyl)amino]benzoic cid), but significantly lower activity than melphalan, a commercial mustard drug with a structure resembling tyrosine, occasionally used in the treatment of melanoma., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)